Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Brazil.
Postgraduate Program in Public Health, Universidade Federal do Rio Grande, Rio Grande, Brazil.
Mutat Res Rev Mutat Res. 2022 Jul-Dec;790:108428. doi: 10.1016/j.mrrev.2022.108428. Epub 2022 Jul 27.
Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis ascertainment based on WES is highly dependent on de novo mutations (DNMs) and variants of uncertain significance (VUS). The quantification of DNM frequency in ID molecular diagnosis ascertainment and the biological mechanisms common to genes with VUS may provide objective information about WES use in ID diagnosis and etiology. We aimed to investigate and estimate the rate of ID molecular diagnostic assessment by WES, quantify the contribution of DNMs to this rate, and biologically and functionally characterize the genes whose mutations were identified through WES. A PubMed/Medline, Web of Science, Scopus, Science Direct, BIREME, and PsycINFO systematic review and meta-analysis was performed, including studies published between 2010 and 2022. Thirty-seven articles with data on ID molecular diagnostic yield using the WES approach were included in the review. WES testing accounted for an overall diagnostic rate of 42% (Confidence interval (CI): 35-50%), while the estimate restricted to DNMs was 11% (CI: 6-18%). Genetic information on mutations and genes was extracted and split into two groups: (1) genes whose mutation was used for positive molecular diagnosis, and (2) genes whose mutation led to uncertain molecular diagnosis. After functional enrichment analysis, in addition to their expected roles in neurodevelopment, genes from the first group were enriched in epigenetic regulatory mechanisms, immune system regulation, and circadian rhythm control. Genes from uncertain diagnosis cases were enriched in the renin angiotensin pathway. Taken together, our results support WES as an important approach to the molecular diagnosis of ID. The results also indicated relevant pathways that may underlie the pathogenesis of ID with the renin-angiotensin pathway being suggested to be a potential pathway underlying the pathogenesis of ID.
全外显子测序（WES）可用于分子诊断、家族遗传咨询和智力障碍（ID）的预后。然而，基于 WES 的 ID 分子诊断的确定高度依赖于新生突变（DNMs）和意义不确定的变异（VUS）。在 ID 分子诊断中确定 WES 中 DNM 频率的量化以及 VUS 基因的常见生物学机制可能为 WES 在 ID 诊断和病因学中的应用提供客观信息。我们旨在研究和估计 WES 进行 ID 分子诊断评估的比率，量化 DNMs 对该比率的贡献，并对通过 WES 鉴定的突变的基因进行生物学和功能特征分析。进行了一项 PubMed/Medline、Web of Science、Scopus、Science Direct、BIREME 和 PsycINFO 的系统评价和荟萃分析，包括 2010 年至 2022 年期间发表的研究。综述中包括 37 篇使用 WES 方法进行 ID 分子诊断产量的研究文章。WES 检测的总体诊断率为 42%（置信区间（CI）：35-50%），而仅限于 DNMs 的估计值为 11%（CI：6-18%）。提取并将突变和基因的遗传信息分为两组：（1）用于阳性分子诊断的突变基因，（2）导致不确定分子诊断的突变基因。在功能富集分析之后，除了它们在神经发育中的预期作用外，第一组基因在表观遗传调控机制、免疫系统调节和昼夜节律控制方面富集。不确定诊断病例的基因在肾素血管紧张素途径中富集。总之，我们的结果支持 WES 作为 ID 分子诊断的重要方法。结果还表明了可能与 ID 发病机制相关的相关途径，提示肾素血管紧张素途径可能是 ID 发病机制的潜在途径。
